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“Peptic Ulcers are an Infectious Disease Caused By Helicobacter Pylori” is an Illusion in Medical Research

Submitted:

21 October 2023

Posted:

23 October 2023

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Abstract
Currently, peptic ulcers are widely studied as an infectious disease caused by Helicobacter pylori primarily due to 3 supporting evidences, and this etiology may explain the other 3 observations, but cannot confront the challenges of the 15 major characteristics and the other 75 observations/phenomena of peptic ulcers. To address the challenges, a recently published Complex Causal Relationship with its accompanying methodologies was applied to analyze existing data. Peptic ulcers are identified as a psychosomatic disease triggered by psychological stress, where Helicobacter pylori plays a secondary role in only the late phase of ulceration. This new etiology elucidated all the 15 major characteristics and 81 observations/phenomena of peptic ulcers in a series of 6 articles. This sixth article focuses exclusively on the controversies surrounding the role of Helicobacter pylori in peptic ulcers. In-depth analyses find that all the 3 evidences supporting “peptic ulcers are an infectious disease caused by Helicobacter pylori” are deceiving, and 2 of the 3 explainable observations may have been misinterpreted. Meanwhile, the definitions of ‘etiological factor’ and ‘causality’ do not support ‘H. pylori infection is an etiological factor of peptic ulcers’, and existing literatures have presented a controversial view on the role of Helicobacter pylori in peptic ulcers. Interestingly, if “peptic ulcers are an infectious disease caused by Helicobacter pylori” is considered an illusion, all the characteristics of the disease, along with all the clinical, epidemiological, and laboratory observations/phenomena, can be fully understood. This illusion has misguided peptic ulcer research over the past 36 years with little progress in the field, and that may represent a widespread situation in modern medical research, resulting in a direct interference with the true understanding of disease. Evidently, keeping the concept “illusion” in mind may help remove a huge obstacle that impedes medical advance, thereby facilitating the in-depth study of disease.
Keywords: 
peptic ulcers
;  
pathogenesis
;  
etiology
;  
Helicobacter pylori
;  
illusion
;  
African enigma
;  
psychosomatic disease
;  
psychological stress
Subject: 
Medicine and Pharmacology  -   Gastroenterology and Hepatology

Introduction

Over the past 300 years, 13 etiological theories, such as ‘No Acid, No Ulcer’ [1], Nerve Theory [2], Psychosomatic Theory [3], and Stress Theory [4], have been proposed to explain the pathogenesis of peptic ulcers [5]. Although each of these theories could explain a minority of the 15 major characteristics and 81 observations/phenomena of the disease [5], they failed to explain the majority of these due to their respective inconsistencies [6]. To date, none of these theories can explain the birth-cohort phenomenon [7] and seasonal variation of peptic ulcers [8], along with the morphology and predilection sites, perforation and bleeding, relapse and multiplicity of gastric ulcers [6]. Moreover, although duodenal and gastric ulcers share much in common, they were found to be epidemiologically, behaviourally, and genetically different two diseases [9,10]. However, the similarities and differences between duodenal and gastric ulcers have never been clarified [1].
The isolation of the bacterium Helicobacter pylori (H. pylori) in 1982 dramatically changed the concept of peptic ulcers [11]. In 1987, Marshall proposed that peptic ulcers are an infectious disease caused by the infection of H. pylori [12]. In 1988, Marshall further concluded that ‘C[H]. pylori is the most important etiological factor so far described for duodenal ulcer’ [13]. Currently, it is widely believed that there is a causal relationship between H. pylori and peptic ulcers primarily due to 3 supporting evidences [14]. First, most peptic ulcer patients are infected with H. pylori, and clinical patients have a higher infection rate than the normal population [15,16,17,18]. Second, ulcers are significantly larger in infected rats compared to uninfected, and H. pylori infection delays ulcer healing, which can be resolved by eliminating the bacterium [19,20]. Third, the elimination of H. pylori results in a significant reduction of the ulcer relapse rate [13,17,21]. The etiological theory of peptic ulcers based on H. pylori infection has been designated as Theory of H. pylori [5].
Unfortunately, Theory of H. pylori is not superior to any other etiological theory in history but has led to additional controversies [14,22,23,24,25] and mysteries. Many researchers have questioned the causal role of H. pylori in peptic ulcers, and how H. pylori infection causes peptic ulcers has remained elusive [26] for 36 years after Marshall’s proposal. This theory cannot identify the roles of gastric acid and NSAIDs in the disease [27,28]. Interestingly, this theory could not explain 30 of the 36 observations/phenomena related to the bacterium itself. Moreover, out of all the 81 observations/phenomena of peptic ulcers, 45 were not associated with H. pylori infection [5], making it very difficult for Theory of H. pylori to explain the pathogenesis of peptic ulcers. For example, the ulcer lesions in patients without H. pylori infection is one of the most challenging issues in Theory of H. pylori. In addition, H. pylori is omnipresent in the stomach, but gastric ulcers are a sharply circumscribed loss of tissue located primarily in the gastric antrum and lesser curvature, having a characteristic ‘punch out’ appearance with clean edges, as if it were cut by a knife [10,29]. Thus, Theory of H. pylori has fallen into inconsistency when it was applied to explain the morphology and predilection sites of gastric ulcer, as well as all the other characteristics and the majority of observations/phenomena of peptic ulcers. Furthermore, similar to all the other etiological theories in history, Theory of H. pylori cannot resolve any one of the epidemiological mysteries, such as the birth-cohort phenomenon and seasonal variation, but directly incur a new mystery of peptic ulcers, the African enigma, which states that H. pylori infection is very common in Africa, but the prevalence of peptic ulcers is low and varies regionally [30]. Evidently, the most recent Theory of H. pylori, along with all the other 12 etiological theories proposed in modern medical history, failed to explain the pathogeneis of peptic ulcers.
The challenges in current peptic ulcer research suggest that we may have to explore a new path outside of current medicine. Fortunately, in May 2012, a book entitled Philosophical Principle of Life Science was published, in which a Complex Causal Relationship (CCR) with its accompanying methodologies, epistemologies, and way of thinking was proposed to understand various life phenomena and human diseases [31]. To test the validity of this CCR, peptic ulcers were selected as a model disease to explain, resulting in the birth of a new etiological theory of peptic ulcers, Theory of Nodes [32,33]. This theory integrated the Psychosomatic Theory [3] and Stress Theory [4] proposed in 1950 into a new etiology of peptic ulcers, where peptic ulcers are not an infectious disease caused by H. pylori, but a psychosomatic disease triggered by psychological stress [32]. Encouragingly, this etiology explained all the 15 characteristics and 81 observations/phenomena of peptic ulcers [34], including all the 36 observations/phenomena associated with the bacterium. Moreover, this etiology addressed all the controversies and mysteries related to peptic ulcers, such as the birth-cohort phenomenon [35] and seasonal variation [36], and the morphology and predilection sites [33], as well as the roles of gastric acid, H. pylori, and NSAIDs in the disease [32,33]. The similarities and differences between duodenal and gastric ulcers are also clarified [33]. Due to a limit of words, the data analyses are summarized into a series of 6 articles (Supplementary Table S1). In the first five articles of the series, 14 major characteristics and 73 observations/phenomena of peptic ulcers, most of which have never been fully understood before, have been explicitly elucidated [32,33,34,35,36]. This analysis is the sixth one of the series, aiming to address the controversies surrounding the role of H. pylori in peptic ulcers, along with the mystery of the African enigma.

1. In-depth analyses dispute the 3 supporting evidences of Theory of H. pylori

In Theory of Nodes, H. pylori is not a cause of peptic ulcers, but a risk factor playing a secondary role in only the late phase of peptic ulceration, exacerbating ulcer symptoms, delaying healing process, and increasing clinical morbidity and mortality rates [32,33]. As a result, patients infected with H. pylori are more likely to become clinical patients due to exacerbated symptoms. In contrast, H. pylori-negative patients have milder symptoms and are less likely to seek medical attention. This skews the epidemiological surveys because only patients with severe symptoms tend to see doctors and thus, many H. pylori-negative subclinical patients are excluded from the surveys, causing a much higher infection rate of H. pylori among clinical ulcer patients as calculated in Table 1. This analysis suggests that ‘clinical patients have a higher infection rate than the normal population’ cannot be used to support ‘there is a causal relationship between H. pylori and peptic ulcers’.
Second, any local aggressive factor in the stomach, such as H. pylori, gastric acid, or NSAIDs, may lead to larger ulcer lesions and delay the healing process because they are corrosive to the local tissues. If H. pylori is considered an etiological factor, the other two local aggressive factors, gastric acid and NSAIDs, should also be regarded as etiological factors, further causing controversies and challenges in current research. As elucidated by Theory of Nodes, removing local aggressive factors via antibiotics or anti-secretary drugs mitigates clinical symptoms and accelerates the ulcer healing process, giving clinical doctors an illusion that ‘the patients are cured’. These treatments may turn 60-80% of clinical patients into sub-clinical patients, but in fact, they are not cured because the real cause, psychosomatic factors and psychological stress, which induce the hyperplasia and hypertrophy of gastrin and parietal cells in the stomach [32] or the submucosal nodes in the gastric wall [33], were not removed. Therefore, larger lesions and delayed healing processes by the infection do not imply that there is a causal relationship between H. pylori and peptic ulcers. On the other hand, if peptic ulcers are an infectious disease caused by H. pylori infection, the bacterium should account for the lesions in H. pylori-negative patients, directly resulting in an insurmountable contradiction.
Third, provided H. pylori infection was the primary cause of peptic ulcers, eradication of the bacterium should be able to prevent the relapse. Unfortunately, despite the successful eradication of H. pylori, more than 20% of the patients relapsed [37,38]. The high relapse rate might be a result of re-infection. However, the re-infection of H. pylori is rare, as documented with the long-term rates of re-infection as low as 1% per year in Europe and Australia [17,39,40]. With an average follow-up period of one year, a study in the United States found that only 4 of 118 patients (~3.4%) in whom the eradication of H. pylori was documented became re-infected [17,41]. In Japan, the re-infection occurred in 15 of 274 patients (5.5%) 6 months after eradication and the annual re-infection rate per year was 2.0% [42]. The re-infection rate is much lower than the relapse rate, indicating that the relapse of peptic ulcers cannot be attributed to the re-infection. Rather, it is other factors that cause the relapse of peptic ulcers. Theory of Nodes elucidated that the ‘other factors’ are the pre-existing hyperplasia and hypertrophy of gastrin and parietal cells in the stomach and the formation of submucous nodes in the gastric wall due to psychosomatic factors and the immediate psychological stress, which cannot be removed by anti-acid and antibiotic treatments, resulting in ‘once an ulcer, always an ulcer’ [43,44].
Thus, a higher H. pylori infection rate in clinical patients, larger ulcer lesions and delayed healing process after infection, and a lower relapse rate after bacterial elimination cannot be used to support ‘peptic ulcers are an infectious disease caused by H. pylori’. All the 3 supporting evidences can be explained by ‘H. pylori plays a secondary role in only the late phase of peptic ulcerations, exacerbating clinical symptoms’.

2. Alternative interpretations for two observations explainable by H. pylori

Out of all the 36 observations/phenomena associated with H. pylori, excluding the 3 supporting evidences, three other observations are explainable by Theory of H. pylori. Starting from ‘peptic ulcer is a psychosomatic disease triggered by psychological stress’, Theory of Nodes offers alternative explanations for two of the three observations, further demonstrating the pitfalls of Theory of H. pylori.
In a relatively isolated group of Australian Aboriginals, peptic ulcers were rare [45]; in a 2-year study of Pima Indians in North America, no peptic ulcer was found [46]. In contrast, a high percentage (10%) of the Caucasian population in North America developed peptic ulcers during the same time-period [47]. In Theory of H. pylori, these two observations can be explained by either no infection or a low infection rate of H. pylori in Pima Indians and Australian Aboriginals, or a high infection rate in Caucasians. In contrast, in Theory of Nodes, the low morbidity rates of peptic ulcers in Pima Indians and Australian Aboriginals were not because they had a lower H. pylori infection rate, but because they were living in a pastoral culture with less social conflicts and therefore, they were leading a less stressful life. The higher percentage of peptic ulcers in the Caucasian population was not because of a high infection rate of H. pylori, but because of more conflicts in modern life or civilization, such as financial crisis, unemployment, or interpersonal competition. In addition, Theory of H. pylori can explain ‘a negative interaction between H. pylori and NSAIDs on duodenal ulcers suggests that H. pylori reduces the development of ulcers in NSAIDs users (No. 69 in Supplementary Table S6)’. However, this observation alone does not indicate that “peptic ulcers are an infectious disease caused by Helicobacter pylori”.
Hence, of all the 36 observations/phenomena associated with H. pylori, Theory of H. pylori can explain only 6 (=3+2+1) and falls into inconsistence when it is employed to elucidate all the remaining 30. Unfortunately, none of the 6 explainable observations/phenomena can be used to support “peptic ulcers are an infectious disease caused by Helicobacter pylori”, suggesting that Theory of H. pylori is in fact not supported by any clinical, epidemiological, and laboratory observations/phenomena.

3. Applying historical definition of ‘etiological factor’ or ‘causality’ to H. pylori

Starting from ‘H. pylori plays a secondary role in only the late phase of peptic ulceration’, Theory of Nodes elucidated all the 36 observations/phenomena associated with H. pylori within a series of 6 articles, suggesting that it may have identified the role of the bacterium in peptic ulcers. However, this statement raised a new question: can a factor playing a secondary role in only the late phase be considered an etiological factor of the disease? To answer this question, herein the historical definitions of ‘etiology’ and ‘causality’ are briefly reviewed and applied to the roles of H. pylori in peptic ulcers.
In 1965, Hill proposed 9 criteria to determine causality: strength of the association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence, and analogous evidence [48]. These criteria have been most frequently cited to identify causal relationships between potential factors and disease [49,50]. To address the argument above, herein only ‘temporality’ is applied to the role of H. pylori in peptic ulcers. In support of causality, temporality means ‘in order for a causal factor to result in an outcome, it must precede the occurrence of the outcome in time’ [48]. H. pylori infection neither initiates the disease nor precedes the hypersecretion of gastric acid in duodenal ulcers or the formation of submucous nodes in gastric ulcers but plays a secondary role in only the late phase of peptic ulcerations and thus, it is not an etiological factor of the disease.
In 1986, Wulff depicted etiology or causality as ‘a linear process where upstream causes represent the etiological factors and the causal intermediates represent the pathological process’ [51,52]. When this definition is applied, H. pylori is neither an ‘upstream cause’ nor a causal intermediate but plays a secondary role in only the downstream of the ulceration process. Susser’s definition also suggests that ‘the cause of a disease must precede the effect and occur together with the putative effect’ [53]. However, H. pylori infection neither precedes the abnormal neurotransmitters supported by innumerable neurological studies on peptic ulcers, nor occurs together with the putative effect as suggested by epidemiological data that ~20% duodenal ulcer patients and ~50% gastric ulcer patients are H. pylori-negative [20,28,38,54,55,56]. Witthöft also proposed that ‘only causes that directly initiate the disease process (and therefore necessarily temporarily have to precede the onset of the disease) are considered etiological factors’ [57], further supporting that H. pylori is not an etiological factor of peptic ulcers since the infection does not initiate the disease but fortuitously plays a secondary role in only the late phase of the ulceration process.
Therefore, all the existing definitions of ‘etiology’ and ‘causality’ do not support ‘H. pylori is an etiological factor of peptic ulcers’. Similarly, these definitions are also applicable to gastric acid and NSAIDs. Hence, none of the 3 local aggressive factors in the gastro-duodenum, H. pylori, gastric acid, and NSAIDs, is an etiological factor of peptic ulcers; ‘No Acid, No Ulcer’ [1] and Theory of H. pylori [5], are in fact not etiological theories, but illusions in peptic ulcer research.

4. Existing data presented a controversial view on the role of H. pylori

The above analyses indicate that ‘a causal relationship between H. pylori and peptic ulcers’ [14], or ‘H. pylori is the most important etiological factor for duodenal ulcers [13]’ overstated the roles of H. pylori in peptic ulcers. Consequently, studying H. pylori as an etiological factor would inevitably lead to controversies, as evidenced by numerous published studies over the past 40 years. In fact, many well-supported controversies on the roles of H. pylori in peptic ulcers have been published in multiple peer-reviewed journals.
In 1994, Record and Rubin disputed the causal role of H. pylori in peptic ulcers with 4 facts [23]: 1. Not all patients are infected with the bacterium and the infection rate is lower in patients with severe symptoms resulting in complications than in patients with uncomplicated dyspepsia. 2. Epidemiological studies discovered that in most patients, the bacterium is a fortuitous and non-pathogenic agent. 3. Inoculating the bacterium to animals cannot induce ulcerations, and duodenal ulcer patients are known to be hyper-secretors of gastric acid, but the colonization of H. pylori induces hypochlorhydria. Notably, Dr. Marshall, who discovered the bacterium, drank a concoction made from cultured H. pylori in 1984, “expecting to develop, perhaps years later, an ulcer”. However, he did not develop a peptic ulcer, but suffered from gastritis that could be cured with antibiotics [58]. 4. Eradicating the bacterium does not cure the disease. In a follow-up study, 48% of patients relapsed within 6 months of healing after eradicating the bacterium [59]. Based on these facts, Record and Rubin concluded that H. pylori was not a causative agent of peptic ulcers [23].
In 1995, Rauws and Tytgat reviewed evidence that was both supporting and opposing ‘H. pylori is an etiological factor for peptic ulcers’ [60]. They found that the association between H. pylori and ulcer disease was non-specific, since not all ulcer patients were H. pylori-positive, and many infected individuals never developed an ulcer. They believed that “most probably, H. pylori infection is necessary, but other factors are required for an ulcer to develop”. They hypothesized that an increased risk of ulcer with increased density of H. pylori infection would strongly support a cause-effect relationship, but only the presence of duodenal ulcers, and not gastric ulcers, was associated with increasing H. pylori density [61]. Moreover, if H. pylori-induced gastritis is a cause of ulceration, it would be challenging to explain why gastritis is in the stomach, but the ulcer occurs in the duodenum. Furthermore, H. pylori infection could not explain the African enigma [30] and why duodenal ulcers had a higher incidence in large cities than in rural areas. Rauws and Tytgat believed that a strong association did not necessarily imply H. pylori was the cause of peptic ulcer disease [60].
Tovey and Hobsley listed 4 reasons to disprove ‘H. pylori was the primary cause of duodenal ulcers’ [25]: 1. The infection of H. pylori is uniformly high in developing countries, but the incidence of duodenal ulcers is remarkably different. 2. In countries with a low infection rate, 30-40% of duodenal ulcer patients are H. pylori-negative. 3. H. pylori infection could not be detected in some early cases of duodenal ulcers. 4. In duodenal ulcer patients with antral H. pylori infection, H. pylori is often absent in the duodenum, and a complete eradication of this bacterium could not prevent the relapse of the disease.
There are further data on the controversial role of H. pylori in peptic ulcers. In 2009, Ford and Talley insisted that the association was causal, but Hobsley et al. believed that gastric acid secretion was the key to duodenal ulcers [14,22]. In 2001, Elitsur and Lawrence found that H. pylori and NSAIDs were not the primary etiology for peptic ulcers in children [62]. Linda and Ransohoff believed that a causal relationship between H. pylori and duodenal ulcers could not be established [63]. In 2013, Kate et al. concluded that acid secretion is the most important cause for duodenal ulcers, often combined with reduced mucosal resistance [24]. H. pylori eradication is valuable to the long-term healing, but this does not mean H. pylori infection is the initial or primary cause of the duodenal ulcers [24]. Zelickson’s clinical observation found that, of 82 ulcer patients tested, 49 (60%) were H. pylori-negative, and of all the 128 patients requiring surgery, only 26% had the infection, suggesting H. pylori infection was not a predominant etiological factor of peptic ulcer patients [64].
Evidently, existing data has presented a controversial view on the causal relationship between H. pylori and peptic ulcers [65]. In contrast, when H. pylori infection is not considered an etiological factor of peptic ulcers, Theory of Nodes addressed all the controversies surrounding H. pylori and elucidated all the 36 observations/phenomena associated with the bacterium. Significantly, Theory of Nodes has elucidated that the hyperplasia and hypertrophy of gastrin and parietal cells in the stomach [32] or the pre-existing submucous nodes in the gastric wall [33] account for other unclear factors or the reduced mucosal resistance in the controversies.

5. Epidemiological studies dispute the causal role of H. pylori in peptic ulcers

Epidemiology is an essential tool to assess risk factors for a disease [66,67,68]. If there is ‘a causal relationship between H. pylori and peptic ulcers’, Theory of H. pylori should be able to explain the birth-cohort phenomena [7,69], seasonal variation [8], and African enigma [30], as well as all the other epidemiological observations on peptic ulcers.
The discoverer of the bacterium, Dr. Marshall, could not explain the birth-cohort phenomenon of peptic ulcers by himself [70]. Sonnenberg’s mathematical model in 2006 also had evident defects while explaining this phenomena [71]. Other studies attempted to explain the birth-cohort phenomenon by citing the mutation between different strains of H. pylori, such as cag- and cag+ [72,73,74,75,76]. However, for this to explain the birth-cohort phenomenon, at the start of the World War I, H. pylori would have to mutate to a more virulent strain (cag+) and then upon the resolution of the World War II, revert to a less virulent strain (cag-). This does not follow natural bacterial evolution. Moreover, the birth-cohort phenomenon is not an independent observation that defines peptic ulcers. If the ‘mutation theory’ is true, then it should explain both the seasonal variation [8] and the African enigma [30]. However, when the ‘mutation theory’ was used to explain these two phenomena, a fantastic conclusion would have to be drawn: the bacterium mutated back and forth seasonally or regionally. In addition, the seasonal changes of H. pylori infection were not in parallel with the seasonal variation of peptic ulcers [77,78], and the infection cannot explain the difference in prevalence of H. pylori versus peptic ulcers in Africa, causing the ‘African Enigma’ [30,60]. In short, Theory of H. pylori fails to explain any of the 3 characteristic epidemiological observations of peptic ulcers.
In contrast, based on ‘peptic ulcers are a psychosomatic disease triggered by psychological stress’, Theory of Nodes explained all three epidemiological observations. This theory elucidated that the mortality rates of peptic ulcers are parallel with the psychological impacts of multiple environmental factors, which cause the birth-cohort phenomena and seasonal variation by superposition mechanism [35,36]. As per the birth-cohort phenomena, the psychological stress caused by a succession of crucial social events maintained the increased mortality rates from the 1910s to 1940s, whereas the sustained improvements in living environments led to the steady decline of the mortality rates since the early 1950s [35]. Similarly, it is the psychological stress induced by seasonal changes that account for the seasonal variation of peptic ulcers [36]. Interestingly, the mechanism of the birth-cohort phenomenon elucidated by Theory of Nodes is also applicable to understanding the African enigma: it is not the prevalence of H. pylori, but the diverse living and political environments, social welfare, conflicts, etc. determine the regional difference in the prevalence of peptic ulcers. Thus, H. pylori infection is not an etiological factor of peptic ulcers, but it is regarded as an etiological factor by default, resulting in the African enigma [30,60].
In fact, Theory of H. pylori cannot explain any one of the epidemiological observations. First, despite a high prevalence of H. pylori infection, the incidence of peptic ulcers in children was low [62,79]. Second, H. pylori prevalence in gastric ulcer patients was less than 50% [54] and in some countries, up to 40% of duodenal ulcer patients were H. pylori-negative [25]. Third, ~20% of peptic ulcers in the Polish population were not associated with H. pylori infection [20], and in the US, only 27% of symptomatic children with peptic ulcers were H. pylori-positive [62]. Fourth, autopsy reports from three European countries suggested that 20-29% of males and 11%-18% of females had unknowingly suffered from ulcers [80,81,82]. Finally, duodenal ulcers had higher incidence rates in large cities than in rural areas [83,84]. This list further exemplifies the controversies surrounding H. pylori as an etiological factor of peptic ulcers.
Theory of Nodes fully addressed all the epidemiological observations. The occurrence of peptic ulcers is not determined by H. pylori infection, but by the hyperplasia and hypertrophy of gastrin and parietal cells in stomach or the negative life-view induced by psychosomatic factors in early life [32,33]. Only those affected by psychosomatic factors and psychological stress become ulcer patients [32,33], explaining a high prevalence of H. pylori infection, but a low incidence of peptic ulcers. The H. pylori-negative gastric and duodenal ulcer patients (50% and 40%, respectively [25,54]) also support the conclusion of Theory of Nodes that H. pylori is not an etiological factor of peptic ulcers. In addition, only 27% of symptomatic children with peptic ulcers were H. pylori-positive [62], indicating ulcers in 73% of younger patients are not associated with the bacterium because they encounter less opportunities of exposure to infection in their short lifetime. From 1900’s to 1950’s, men were more likely to be the direct participants of social conflicts, such as wars and financial crisis, and they were more likely to bear economical pressures than women, supporting the autopsy findings that a higher percentage of males (20-29%) than females (11%-18%) had unknowingly suffered from ulcers. A more stressful life with highly intensive social competition explains the higher incidence of peptic ulcers in large cities as compared to rural areas.
Therefore, H. pylori infection cannot explain any one of the epidemiological observations associated with peptic ulcers. In contrast, if peptic ulcers are considered a psychosomatic disease triggered by psychological stress, all the epidemiological observations and mysteries can be fully understood, further suggesting that H. pylori infection is not the cause of the disease.

6. Characteristics of peptic ulcers dispute the causal role of H. pylori in this disease

If H. pylori infection is considered an etiological factor of peptic ulcers, none of the 15 major characteristics of this disease, including the one associated with the bacterium itself, can be fully explained. In contrast, when peptic ulcers are considered a psychosomatic disease triggered by psychological stress, all the 15 major characteristics of peptic ulcers, as well as the role of H. pylori in the disease, can be fully elucidated.
First, Theory of H. pylori cannot explain the predilection sites and morphology of gastric ulcers. The H. pylori density was significantly higher in the incisura angularis, which is located not on the gastric antrum, but on the lesser curvature of the stomach [85]. However, gastric ulcers are more likely to occur not in the lesser curvature, but in the gastric antrum. Moreover, since H. pylori is omnipresent in the stomach, all regions of the stomach should have the chance to ulcerate, but gastric ulcers have a predilection site in the gastric antrum and lesser curvature, and a characteristic ‘punch out’ appearance with clean edges, as if it were cut by a knife [10,29]. In contrast, Theory of Nodes dictates that the predilection sites of gastric ulcers are determined by the location where the submucosal nodes occur, which is determined by the nerve density in the stomach. Compared to other parts of the stomach, the gastric antrum and lesser curvature have the largest ganglions and the highest density of developed nerve plexus [86]. Thus, they receive more pathogenic nerve impulses from the CNS than other parts of the stomach, thereby becoming the predilection sites of gastric ulcers. The spherical shape of the submucosal nodes gives gastric ulcers a characteristic ‘hole-punch’ shape [33].
Second, H. pylori infection cannot explain the relapse, multiplicity, and self-healing of peptic ulcers. If H. pylori was the cause of ulcers, eliminating this bacterium should prevent the relapse, but in fact, numerous data indicates that a complete eradication of the bacterium cannot prevent the relapse [37,42,87,88]. As a result, Theory of H. pylori fails to explain ‘Once an Ulcer, Always an Ulcer’. Moreover, Theory of H. pylori cannot explain why at times an individual ulcer appears and at other times, they occur in multiples. In Theory of Nodes, as long as the negative impacts of psychosomatic factors and psychological stress continue to exist, the relapse of peptic ulcers will be inevitable, resulting in ‘Once an Ulcer, Always an Ulcer’. Thus, it is the relapse and multiplicity of submucous nodes in the gastric wall that determine the relapse and multiplicity of gastric ulcers [33]. The solitude and/or multiplicity of submucous nodes are determined by the local neuroanatomy in the stomach, which may vary individually. In Theory of Nodes, peptic ulcers heal automatically via the regeneration of the local tissue, like a wound healing on the skin, but the local aggressive factors, gastric acid, H. pylori, and NSAIDs, may delay the healing process.
Third, Theory of H. pylori cannot explain the bleeding and perforation of peptic ulcers. It cannot explain a lower prevalence of H. pylori infection in patients with bleeding peptic ulcers [89,90]. A study found that 62% of patients with perforated peptic ulcers were H. pylori-positive, but the infection was detected in 87% of ulcer patients without this complication [91]. In Theory of Nodes, the bleeding and perforation indicates the patients are severely impacted by psychological stress, causing higher hypersecretion of gastric acid for duodenal ulcers and larger submucous nodes for gastric ulcers. If large blood vessels are close to or within the nodes, they rupture during ulceration, causing bleeding. If the nodes are deep in the serosa, the ulcer will penetrate deep into the serosa, resulting in the perforation of gastric ulcers. In contrast, the patients without the complication of bleeding and perforation are more likely to be subclinical ulcer patients if not infected with H. pylori. It is the infection that turns the subclinical ulcer patients into clinical patients. Thus, mildly symptomatic clinic patients are more likely to be infected with the bacterium. In this case, the percentage of H. pylori-infected patients without complications is higher than the percentage of H. pylori-infected patients with bleeding and perforation.
Fourth, the different etiology, epidemiology and genetics of gastric versus duodenal ulcers indicate that although gastric and duodenal ulcers share some common features, they are two different diseases [10,66]. Theory of H. pylori cannot describe the similarities and differences between gastric and duodenal ulcers. In contrast, without taking H. pylori infection into consideration, Theory of Nodes clearly identified the similarities and differences between the two diseases [34]. Both are a psychosomatic disease triggered by psychological stress due to specific personality traits and/or stressful life events, which lead to abnormal neurotransmitters in the central nervous system and pathogenic nerve impulses to the stomach. However, duodenal and gastric ulcer patients are genetically different individuals in the population. The effector organs of both diseases are the stomach, but duodenal ulcers are characterized by the hypersecretion of gastric acid, whereas gastric ulcers are characterized by immediate formation of submucosal nodes in the gastric wall. Additionally, Theory of H. pylori cannot explain why all the stress-induced ulcers in the lab are gastric ulcers, and how chemicals can induce duodenal ulcers in normal rats without the presence of H. pylori [92]. In contrast, Theory of Nodes elucidates that animal models can only simulate acute stress, which merely causes gastric ulcers, and chemicals interact directly with the effector organs of stress-induced pathogenic nerve impulses, resulting in hypersecretion and eventually, duodenal ulcers. In that case, H. pylori is not essential for duodenal ulcerations.
Fifth, many peptic ulcer patients, but not all, were infected with H. pylori. As a result, the infection is an important characteristic of this disease and is currently a hot topic in peptic ulcer research. However, Theory of H. pylori cannot explain why only the presence of duodenal ulcers was associated with H. pylori density, whereas the association between gastric ulcers and H. pylori is less clear [61]. Theory of Nodes dictates that duodenal ulceration is caused by a superposition of all local aggressive factors in the duodenum. The higher the density of H. pylori, the higher the local aggressive intensity that erodes the duodenal bulbs. Therefore, the increasing density of H. pylori is associated with the presence of duodenal ulcers. In contrast, gastric ulceration is determined by the formation of submucosal nodes, not the local aggressive factors, leading to the significantly weaker association between gastric ulcers and H. pylori infection.
Sixth, since H. pylori is not an etiological factor for peptic ulcers, Theory of Nodes predicts that animal models for the disease induced by H. pylori alone cannot be established. Studies showed that although H. pylori infection in rats has been established, the inoculation could induce only mild to moderate mucosal inflammation, and that ulcers could be induced in the oxyntic mucosa of both infected and uninfected rats by exposing the serosal side to acetic acid [19]. Interestingly, Dr. Marshall drank a concoction made from cultured H. pylori and came down with gastritis that could be cured with antibiotics [93]. He did not develop peptic ulcers as expected, but gastritis only, also suggesting that the infection of H. pylori is not the cause of peptic ulcers.

7. Historical observations/phenomenon dispute the role of H. pylori in peptic ulcers

Although the 5 major etiological theories in history cannot explain the pathogenesis of peptic ulcers, they were supported by numerous valid clinical, laboratory, and epidemiological observations, and did make important discoveries for this disease. These historical observations/phenomena, including those associated with H. pylori, can be used to test if there is a causal relationship between H. pylori and peptic ulcers.
First, it is challenging for Theory of H. pylori to explicate the data originated from both Psychosomatics Theory and Stress Theory. Theory of H. pylori cannot withstand the results from a multi-dimensional case-controlled study in 1986, which discovered a strong association between life events, psychosocial factors and ulcer disease, and ulcer patients exhibited significantly more emotional distress in forms of depression and anxiety [94]. Theory of H. pylori also cannot explain why stressful life events frequently precede the onset of ulcer symptoms in both newly diagnosed and chronic ulcer patients, and ulcer symptoms subside after stressful life events are resolved [95,96]. There is also no relationship between H. pylori and the crucial social events that occurred in the first half of the 20th century, thought by Susser and Stein to cause the birth-cohort phenomenon of peptic ulcers [7,97]. In contrast, Theory of Nodes elucidated that in the pathological process of peptic ulcers, life events/stress occur in the early phase (upstream) of the disease, whereas H. pylori is in the late phase (downstream) of disease, exacerbating clinical symptoms. Notably, if H. pylori infection is considered an etiological factor of peptic ulcers, none of the observations/phenomena in psychological research can be elucidated.
Second, studies from Nerve Theory suggested that peptic ulcers were a ‘brain-driven’ event [98,99], and the central noradrenergic system was activated when animals were subject to ulcerogenic stress procedures [98,99,100,101,102]. Gastric ulceration was linked with the enhancement of calcium/calmodulin-dependent catecholamine synthesis in the brain as indicated by the observations that pre-treatment with intraperitoneal EDTA (calcium-chelator) or CaCl2 significantly decreased or increased gastric ulcers induced by cold stress, respectively [101]. Moreover, the amygdala might be the brain site for modulating stress-induced gastric erosions [98,103,104], and manipulation of the central nucleus of the amygdala may produce gastric ulcers [98,103,105,106]. In addition, many peptic ulcer patients have psychological symptoms such as anxiety, irritability, depression, or poor appetite [107,108,109]. None of these findings can be elucidated by Theory of H. pylori. Theory of Nodes elucidated that the neurological observations discovered the intermediate phase (midstream) of peptic ulcerations, whereas H. pylori infection is in the downstream (late phase). Unequivocally, the midstream neurological process is not caused by the downstream H. pylori infection.
Third, duodenal ulcer patients have increased basal and maximal acid secretion, whereas most gastric ulcer patients are normo- or hypo-secretors [110,111]. Hence, Schwartz’s dictum ‘No Acid, No Ulcer’ remains true only for duodenal ulcers [112]. If H. pylori is an etiological factor for peptic ulcers, then Theory of H. pylori should be able to explain the differences in gastric acid secretion between duodenal and gastric ulcers. However, Theory of H. pylori cannot explain all these clinical findings [95]. If H. pylori was the most important etiological factor for duodenal ulcers as stated by Marshall, H. pylori infection should account for the hypersecretion of gastric acid, but on the contrary, H. pylori infection was found to suppress gastric acid secretion, causing increased pH of gastric juice [95], and no consistent hypersecretion of gastric acid was observed after H. pylori infection [113,114]. Theory of Nodes fully elucidated the differential relationship of gastric acid in duodenal versus gastric ulcers, which had no causal relationship with H. pylori infection. Duodenal ulceration results from the superposition of all local aggressive factors in the gastro-duodenum, where the hypersecretion of gastric acid due to psychosomatic factors in early life determines all the local characteristics of the disease, and this agrees with the findings that duodenal ulcer patients have increased basal and maximal acid secretion [112,115]. In contrast, gastric ulceration is determined not by any of the local aggressive factors in the stomach, such as H. pylori, gastric acid, and NSAIDs, but by the formation of submucosal nodes in the gastric wall, and this is supported by the findings that most of gastric ulcer patients are normo- or hypo-secretors.
A comprehensive literature review on peptic ulcers found that the research originated from Psychosomatics Theory, Stress Theory, Nerve Theory, and ‘No Acid, No Ulcer’ did make important discoveries on peptic ulcers [5]. Therefore, the historical data from 1900 to 1990 is indispensable for a full understanding of the etiology and pathogenesis of peptic ulcers. However, all these important historical findings were overshadowed by Marshall’s proposal that ‘peptic ulcers are an infectious disease caused by H. pylori’.

8. The comparative effectiveness research identified an illusion in medicine

The data analyses above suggest that, if peptic ulcers are considered an infectious disease caused by H. pylori, none of the 15 major characteristics can be fully understood, and 75 of the 81 observations/phenomena remain elusive. What is more, this etiology has led to more controversies and mysteries than the other etiological theories of the disease. In contrast, if peptic ulcers are considered a psychosomatic disease triggered by psychological stress, all the 15 major characteristics and 81 observations/phenomena can be fully addressed in a series of 6 articles, along with all the controversies and mysteries associated with this disease (Supplementary Table S1-S6). This sixth article explained 8 observations/phenomena (Supplementary Table S5-S6). A detailed comparison between Theory of H. pylori and Theory of Nodes is curated into Table 2.
An etiological theory proposing the correct cause should be able to explain all the characteristics and observations/phenomena of the disease [5]. The comparative analysis in Table 2 suggested that the 15 major characteristics and 81 observations/phenomena of peptic ulcers cannot be fully understood unless the disease is considered a psychosomatic disease triggered by psychological stress as demonstrated in Theory of Nodes. The effectiveness suggests that Theory of Nodes may have identified the etiology of peptic ulcers, in which H. pylori infection is not the cause but was studied as the (primary) cause of the disease. As a result, little progress has been made in peptic ulcer research over the past 36 years, and eradication of the bacterium cannot prevent the relapse [37,42,87,88]. This kind of error may widely exist in the research on almost all diseases. Consequently, so far, no disease has been fully understood in modern medicine. Thus, it is essential to introduce an important concept, illusion, to the medical community, wherein an idea, belief, or impression may appear convincing but is in fact misleading and results in misdirection.
If ‘peptic ulcers are an infectious disease caused by H. pylori’ is considered an illusion in the field, it is easy to understand why Theory of Nodes cannot explain all the 15 major characteristics and the majority of 81 observations/phenomenon but cause more controversies and mysteries. This illusion was a direct interference with the true understanding of peptic ulcers for more than 3 decades. First, due to this illusion, the real cause of peptic ulcers, proposed by Psychosomatic Theory and Stress Theory in 1950, was discredited, and the field of research was misdirected to focus on the infection of H. pylori [125]. The data analyses in Theory of Nodes suggests that Psychosomatic Theory and Stress Theory could not explain the pathogenesis of peptic ulcers for the past 70 years, primarily because the methodology, epistemology, and way of thinking essential for data analyses have never been established in modern medicine. Second, also due to the H. pylori illusion, Nerve Theory and ‘No Acid, No Ulcer’, which were proved to have uncovered important intermediate processes for a full understanding of peptic ulcers in Theory of Nodes, were also considered outdated in modern medicine. Third, this tunnel vision (H. pylori illusion) also resulted in the failure of establishing effective analytical methods to address multiple mysteries, such as the birth-cohort phenomenon and seasonal variation of peptic ulcers. It took an unbiased, comprehensive review of historical studies and novel data analyses guided by a new causal relationship (the CCR) with its accompanying methodologies specific for life science and medicine to develop an integrative theory, Theory of Nodes, to fully explain the pathogenesis of peptic ulcers [32,33,34,35,36].

Conclusions

The etiology based on H. pylori infection cannot explain any of the 15 major characteristics and the majority of 81 observations/phenomena of peptic ulcers but has led to more controversies and mysteries. In contrast, if peptic ulcers are considered a psychosomatic disease triggered by psychological stress, all the 15 characteristics and 81 observations/phenomena, along with all the controversies and mysteries associated with peptic ulcers, can be fully addressed. The tremendous contrast suggests that peptic ulcers are not an infectious disease caused by H. pylori, but a psychosomatic disease triggered by psychological stress. Moreover, the definitions of ‘etiological factor’ and ‘causality’ do not support ‘H. pylori is an etiological factor of peptic ulcers’, and the existing literatures have also presented a controversial view on the causal role of H. pylori in peptic ulcers. Meanwhile, the epidemiological studies, major characteristics of the disease, and historical observations indicate that ‘peptic ulcers are an infectious disease caused by H. pylori’ is an illusion in medical research. This illusion discredited useful discoveries from other theories and misdirected peptic ulcer research to focus on H. pylori infection. Consequently, very little progress has been made in the field over the past 36 years, suggesting that medical doctors should always keep the concept of illusion in mind.

Supplementary Materials

The supplemental materials include 6 tables in a PDF document.

Author Contributions

SXMD is the sole author of this article, who conceived the idea, collected and analyzed data, interpreted the data analyses into the table and figures, and drafted the manuscript.

Funding Statement

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Data Availability Statement

All the supporting data in this article are published papers or books, or in the online supporting information.

Acknowledgements

Special thanks to Katelynn J. Rowe, who contributed time and effort to challenge the ideas, optimize the structure, and enrich the contents of the article. I would also like to thank Dr. Xiao Xiang and Dr. Stephen Holland for their constructive comments.

Conflict of Interest

The author has no conflict of interest to report.

Ethics Statement

This study was conducted with integrity, fidelity, honesty, and did not involve any human or animal specimen.

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Table 1. Clinical patients have higher infection rates due to exacerbated symptom.
Table 1. Clinical patients have higher infection rates due to exacerbated symptom.
HP-
(100 individuals)		 HP+
(100 individuals)		 HP- & HP+
(200 individuals)
Actual number of patients 20 20 40
Number of subclinical patients 15* 5* 20*
Number of clinical patients 5** 15** 20**
Clinical morbidity rates 5% 15% 10%
Infection rates of clinical patients = 15 ÷ (5 + 15) = 15 ÷ 20c × 100% = 75% >
H. pylori infection rates in the population = 100 ÷ 200 × 100% = 50%
The infection rate of H. pylori in a population is assumed to be 50%, and 100 individuals were analyzed in H. pylori-positive and negative groups, respectively. H. pylori infection exacerbates the symptoms of peptic ulcers and therefore, infected individuals are more likely to see doctors and become clinical patients (15 vs 5), causing a higher infection rate of H. pylori in clinical patients than that in the normal population (75% > 50%). * These subclinical patients (15 + 5 = 20) were excluded from the calculation of the clinical infection rate of H. pylori. ** Only clinical patients (5 + 15 = 20) were included in the calculation of the clinical infection rate of H. pylori.
Table 2. A comparison between Theory of H. pylori and Theory of Nodes.
Table 2. A comparison between Theory of H. pylori and Theory of Nodes.
Etiological Theory Theory of H. Pylori [12] Theory of Nodes [32,33,34,35,36]
15 characteristics [5] None of the 15 can be explained All the 15 are fully explained
Etiology Peptic ulcers are an infectious disease caused by the infection of H. pylori [12]. Peptic ulcers are a psychosomatic disease triggered by psychological stress [32].
Morphology of gastric ulcers [116] Remains unknown Explained, the only phenomenon needs to be verified [33].
Predilection sites of gastric ulcers [117] Remains unknown Explained [33].
Relapse and Multiplicity [87,118] Remains unknown Explained [33].
Bleeding and Perforation [119] Remains unknown Explained [33].
Epidemiology 3 observations/phenomena were used as supporting evidences [17]; it might be able explain the other 3 observations. All the others remain unexplained. All explained [32,33,34,35,36]. All 3 supporting evidences in Theory of H. pylori were identified as illusions, and the other 3 H. pylori explainable observations were mis-interpreted in Theory of H. pylori.
81 observations/
Phenomenon [5]		 75 of 81 cannot be explained; 45 are unrelated to H pylori. All 81 are explained; leaves no observations/phenomena unknown
36 observations/phenomena
associated with H. pylori 		30 of 36 cannot be explained. All 36 are explained [32,33,34,35,36].
45 observations/phenomenon not associated with H. pylori None can be explained because many patients are H. pylori-negative [38,54,55]. All 45 are explained [32,33,34,35,36].
4 Controversies None of the 4 is addressed All 4 are addressed clearly
Roles of H. pylori Controversial [14,22,23,24,25] Addressed: H. pylori is not an etiological factor but plays a secondary role in only the late phase of ulceration [32,33,34].
Roles of gastric acid Unknown and controversial [14,112] Addressed [32,33].
Roles of NSAIDs Unknown [28,56,73,120,121,122,123] Addressed [32,33].
Idiopathic peptic ulcers Unknown [20,28,56] Addressed [32,33].
3 Major Mysteries None of the 3 is resolved All 3 are resolved clearly.
Birth-cohort Phenomena [69,124] Remains a mystery [69,70] Resolved [35].
Seasonal Variations [8] Remains a mystery Resolved [36].
African Enigma [30] Remains a mystery Resolved in this article: identified as an illusion due to incorrect etiology.
Similarities and differences between gastric and duodenal ulcers [9,10] Remains unknown. Fully illustrated [33].
Therapy/effect Antiacid and antibiotics treatments are the primary therapy; relapse frequently Psychological treatments are the primary therapy; no relapse [34].
Summary
  • Theory of H. Pylori cannot fully explain the pathogenesis of peptic ulcers.
  • H. Pylori infection cannot explain any one of the 15 characteristics and 75 of 81 observations/phenomena of peptic ulcers.
  • Not superior to any other etiological theory in history but has led to more controversies and mysteries.
  • Theory of Nodes explained the pathogenesis of peptic ulcers.
  • This etiological theory leaves no characteristics, observations/phenomena, controversies, and mysteries of peptic ulcers unknown.
  • A causal relationship between H. pylori and peptic ulcers is a typical illusion in modern medicine.
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